Compounds of formula A ##STR4##
wherein
R.sup.1 is hydrogen, C.sub.1-6 -alkyl, C.sub.1-6 -alkyl substituted by fluoro, or C.sub.3-6 -cycloalkyl; PA1 X is CH or N, and PA1 R.sup.5 is hydrogen, PA1 R.sup.1 is hydrogen, C.sub.1-6 -alkyl, C.sub.1-6 -alkyl substituted by fluoro, or C.sub.3-6 -cycloalkyl; PA1 R.sup.2 is hydrogen or a substituent selected from the group consisting of --CH.sub.2 C(.dbd.CHR)--COOR, --CH.sub.2 OCOR, --CH(R)OCOR, --CH(R)OCOOR, --CH(OCOR)OCOR, --CH.sub.2 COCH.sub.2 OCOR and ##STR6## PA1 R.sup.3 is hydrogen or a substituent selected from the group consisting of --CH.sub.2 C(.dbd.CH.sub.2)--COOR, --COOCH.sub.2 C(.dbd.CHR)--COOR, --COOCH.sub.2 OCOR, --COOCH(R)OCOR, --COOCH(R)OCOOR, --COOCH(OCOR)OCOR, --COOCH.sub.2 COCH.sub.2 OCOR, and ##STR7## PA1 with the proviso that one of R.sup.2 and R.sup.3 is hydrogen and the other is not hydrogen, PA1 R is hydrogen or C.sub.1-6 -alkyl; PA1 R.sup.4 is hydrogen or hydroxy, PA1 R.sup.5 is hydrogen or .omega.-hydroxyalkyl; and PA1 X is CH or N, PA1 (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-(R)-1'-(5-ethyl-2-oxo-[1,3]dioxol4-ylmethoxycarbonyl)-2-oxo-[1,3' ]bipyrrolidinyl-3-ylidenemethyl]-8-oxo5-thia-1-aza-bicyclo[4.2. 0]oct-2-ene-2-carboxylic acid sodium salt (1:1); PA1 (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3yl)-2-hydroxyimino-acetylamino ]-3-[(E)-(R)-1'-(2-oxo-5-propyl -[1,3]dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemeth yl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1: 1); PA1 (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-(R)-1'-(5-isopropyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)-2-oxo- [1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2. 0]oct-2-ene-2-carboxylic acid sodium salt (1:1); PA1 (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-(R)-1'-(5-tert-butyl-2-oxo-[1,3]dioxol4-ylmethoxycarbonyl)-2-oxo- [1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2. 0]oct-2-ene-2-carboxylic acid sodium salt (1:1); PA1 (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-(R)-1'-(E-2-isobutoxycarbonyl-pent-2-enyloxycarbonyl)-2-oxo-[1,3' ]bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2. 0]oct-2-ene-2-carboxylic acid sodium salt (1:1); PA1 (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-(R)-1'-(2-ethoxycarbonyl-allyl)-2-oxo-[1,3']bipyrrolidinyl-3-ylid enemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1); PA1 (6R,7R)-7-[(Z)-2-(5-Amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-5'-hydroxymethyl-1'-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbon yl)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid sodium salt; and PA1 (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylamin o]-3-[(E)-(3'S,4'S)- and -(3'R,4'R)-4'-hydroxy-1'-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)- 2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2. 0]oct-2-ene-2-carboxylic acid sodium salt.
and pharmaceutically acceptable salts thereof, especially (6R,7R)-7-[(Z)-2-(5-amino-[1,2,4]thiadiazol-3-yl)-2-hydroxyimino-acetylami no]-8-oxo-3-[(E)-(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-5-thia-1-a za-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, are potent antibacterial agents with activity against methicillin resistant staphylococci, both in vitro and in vivo. However, these compounds have limited solubility, not allowing bolus injections. It is therefore necessary to find derivatives of the compounds A to render these compounds suitable for parenteral and intramuscular application.
From J. Med. Chem. (1996), 39(2), 480-6; U.S. Pat. No. 5,466,81 1; Bioorganic and Medicinal Chem. Left. 1997,7,2909-2912; U.S. Pat. No. 5,610,314 (oxodioxolenyl)methyl carbamates are known to form derivatives of amines e.g. for fibrinogen receptor antagonists, ampicillin, norfloxacin and other pharmaceuticals. Furthermore, 2-(alkyloxycarbonyl)-2-alkylideneethyl esters have been described as prodrugs of carboxylic acids for cephalosporins, J. Antibiot. (1992), 45(8), 1358-64. Both types of derivatives have been used to improve the oral bioavailability of the corresponding drugs.